To date this project has made a number of contributions to our knowledge of metastatic breast cancer. First, it demonstrated that the dissemination of tumor cells has a significant inherited component, contrary to the conventional theory that metastasis resulted from a purely somatic evolutionary process. Second, the first metastasis susceptibility gene, Sipa1, was identified in mouse models and was subsequently demonstrated to be associated with progression in human populations as well. Third, a number of additional genes were discovered that also contribute to human metastatic susceptibility. Genetic analysis of these genes has revealed the presence of at least two different mechanisms for metastatic spread. Most recently the laboratory has incorporated this data into systems biology analysis of metastasis mechanisms. Using new computational tools and large gene expression data sets from both mouse models and human cancer patients our laboratory has identified networks of co-regulated genes that predict metastatic progression. Furthermore, analysis of these networks reveals that there are both tumor autonomous and tumor non-autonomous mechanisms associated with predisposition to develop distant metastases. Interestingly, these mechanisms appear to be mutually exclusive depending on the estrogen receptor status of the tumor. Tumor autonomous factors appear to be important in establishing metastatic predisposition in estrogen receptor-positive breast cancers, while tumor non-autonomous factors play a role in estrogen receptor-negative tumors. This data, combined with our earlier studies suggesting that different metastatic mechanisms exist for lymph node-positive or ?negative tumors suggest that there may be as many as four different pre-disposition mechanisms associated with breast cancer progression. Further characterization of this mechanism should provide additional information to allow better stratification of human breast cancer patients for better selection of therapeutic intervention.In addition to the network analysis, the Hunter laboratory is continuing to identify and characterize individual genes associated with metastatic susceptibility. Recent work has identified several additional candidate genes. Intriguingly, although these genes were identified in independent studies, recent biochemical analyses suggest that the majority of the proteins are nuclear, and may potentially be forming either a single large multi-subunit complex, or may be involved in a series of related modular complexes. Functional analysis of these complexes also suggests that these complexes are likely to be associated with establishment and/or maintenance of chromatin structure and transcription. These results indicate that there may be a central mechanism associated with metastatic progression in the model of estrogen receptor-positive luminal breast cancer model that is the basis of the Hunter laboratory research program. In addition, since this complex or complexes appear to be associated with epigenetic regulation of the genome, these results suggest that metastatic susceptibility might be subject to regulation pharmacologically, using agents like histone acetylation inhibitors. If so, then this opens up the possibility that the burden of metastatic disease might be at least partially ameliorated prospectively, using chemoprevention strategies. Based on these possibilities Hunter laboratory is currently investigating the role of the metastasis susceptibility complex(es) and the potential use of recently developed BET inhibitors as anti-metastatic compounds.